Patrick C Dolder1, Yasmin Schmid1, Felix Mller2, Stefan Borgwardt2 and Matthias E Liechti*,1
1
Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel,
Basel, Switzerland; 2Department of Psychiatry (UPK), University of Basel, Basel, Switzerland
Lysergic acid diethylamide (LSD) is used recreationally and has been evaluated as an adjunct to psychotherapy to treat anxiety in patients
with life-threatening illness. LSD is well-known to induce perceptual alterations, but unknown is whether LSD alters emotional processing
in ways that can support psychotherapy. We investigated the acute effects of LSD on emotional processing using the Face Emotion
Recognition Task (FERT) and Multifaceted Empathy Test (MET). The effects of LSD on social behavior were tested using the Social Value
Orientation (SVO) test. Two similar placebo-controlled, double-blind, random-order, crossover studies were conducted using 100 g LSD
in 24 subjects and 200 g LSD in 16 subjects. All of the subjects were healthy and mostly hallucinogen-naive 25- to 65-year-old volunteers
(20 men, 20 women). LSD produced feelings of happiness, trust, closeness to others, enhanced explicit and implicit emotional empathy on
the MET, and impaired the recognition of sad and fearful faces on the FERT. LSD enhanced the participants desire to be with other people
and increased their prosocial behavior on the SVO test. These effects of LSD on emotion processing and sociality may be useful for
LSD-assisted psychotherapy.
Neuropsychopharmacology (2016) 41, 26382646; doi:10.1038/npp.2016.82; published online 22 June 2016
INTRODUCTION
The classic serotonergic psychedelic/hallucinogen lysergic
acid diethylamide (LSD) was widely studied in humans in
the 1950s to 1970s. However, little to no clinical research on
LSD has been conducted since then (Nichols, 2016; Passie
et al, 2008). Today, LSD is again the focus of clinical
investigations, including experimental studies in healthy
subjects (Carhart-Harris et al, 2016,2015; Dolder et al, 2015b;
Schmid et al, 2015; Strajhar et al, 2016), and clinical trials that
evaluate LSD-assisted psychotherapy (Gasser et al, 2014).
LSD that was administered only a few times decreased
anxiety and increased quality of life over a period of
12 months in patients with anxiety associated with terminal
illness (Gasser et al, 2015). The acute LSD experiences were
hypothesized to lead to a restructuring of the person's
emotional trust and situational understanding (Gasser
et al, 2015). Similar to LSD, the serotonergic hallucinogen
psilocybin and serotonin (5-hydroxytryptamine (5-HT))
releaser 3,4-methylenedioxymethamphetamine (MDMA;
ecstasy) have been used to facilitate psychotherapy in
clinical trials (Grob et al, 2011; Mithoefer et al, 2010;
Oehen et al, 2013). Psilocybin reduced anxiety at 3 months
*Correspondence: Professor ME Liechti, Department of Biomedicine
and Department of Internal Medicine, Division of Clinical Pharmacology
and Toxicology, University Hospital Basel, Hebelstrasse 2, Basel CH-4031,
Switzerland, Tel: +41 61 328 68 68, Fax: +41 61 265 45 60,
E-mail: matthias.liechti@usb.ch
Received 4 March 2016; revised 26 April 2016; accepted 18 May 2016;
accepted article preview online 1 June 2016
2639
receptor stimulation (Vollenweider et al, 1998). The longterm effects of LSD and psilocybin may be related to their
psychedelic and 5-HT2A receptor activation properties. In
contrast to the psychedelics LSD and psilocybin, MDMA
is considered an empathogen (entactogen) that mainly
enhances positive feelings, empathy, and prosociality
(Hysek et al, 2014a; Kirkpatrick et al, 2014) while having
few hallucinogen-like effects. Additionally, MDMA has been
shown to positively alter emotion processing (Bedi et al,
2010; Hysek et al, 2012,2014a; Kirkpatrick et al, 2012,2014;
Schmid et al, 2014). These acute effects of MDMA on
emotion processing and social behavior may be beneficial
during psychotherapy in the absence of a full psychedelic
peak experience. LSD also produced acute MDMA-like
subjective effects, including greater well-being, happiness,
closeness to others, openness, and trust (Schmid et al, 2015).
Thus, LSD and MDMA may have common effects on the
processing of emotional information with relevance to their
positive acute and possibly long-term effects during
psychotherapy. However, the effects of LSD in tests of
emotion processing are unknown. Therefore, the present
study investigated the acute effects of LSD using the Face
Emotion Recognition Task (FERT) and Multifaceted Empathy Test (MET). The effects of LSD on social behavior
were also evaluated using the Social Value Orientation (SVO)
test. Additionally, we assessed the subjective mood effects of
LSD using Visual Analog Scales (VASs) and the Adjective
Mood Rating Scale (AMRS), vital signs, and adverse effects.
We hypothesized that LSD would impair the recognition of
negative emotions on the FERT and enhance emotional
empathy on the MET and prosociality on the SVO test.
Participants
Forty healthy participants were recruited from the University
of Basel campus via online advertisement. Twenty-four
subjects (12 men, 12 women; 33 11 years old (mean SD);
range, 2560 years) participated in Study 1, and 16 subjects
(8 men, 8 women; 29 6 years old; range, 2551 years)
participated in Study 2. The inclusion and exclusion criteria
Study Procedures
Each study included a screening visit, a psychiatric interview,
two 25-h experimental sessions, and an end-of-study visit.
The experimental sessions were conducted in a quiet
standard hospital patient room. The participants were resting
in hospital beds except when going to the restroom. Only one
research subject and one investigator were present during
the experimental sessions. Participants could interact with
the investigator, rest quietly and/or listen to music via
headphones, but no other entertainment was provided. LSD
or placebo was administered at 0900 hours. The subjects
were never alone during the first 12 h after drug administration, and the investigator was in a room next to the subject
for up to 24 h while subjects were asleep (mostly from 0100
to 0800 hours). Because subjective responses to LSD are
pronounced and peak at 23 h and last up to 12 h (Passie
et al, 2008; Schmid et al, 2015), effects on emotion processing
and prosociality were assessed 5 and 7 h after the 100 and
200 g doses, respectively, when the subjective effects of LSD
amounted to approximately 50% of the peak responses
(Dolder et al, 2015b; Schmid et al, 2015).
Study Drug
LSD (D-LSD hydrate; Lipomed AG, Arlesheim, Switzerland)
was administered in single oral doses of 100 or 200 g. Both
doses are within the range of doses that are taken for
recreational purposes (Passie et al, 2008).
Measures
Facial Emotion Recognition Task. We used the FERT,
which is sensitive to the effects of other psychoactive
Neuropsychopharmacology
2640
RESULTS
Facial Emotion Recognition
The effects of LSD on the FERT are shown in Figure 1. Data
were missing from 2 of the 24 subjects in the 100 g LSD
dose group because of technical problems. LSD impaired the
recognition of fearful faces (main effect of drug: F1,36 = 20.71,
po0.001), with no drug dose interaction. Impairments
were found in both the 100 and 200 g dose groups
compared with placebo (po0.01 and po0.05, respectively).
A significant main effect of drug (F1,36 = 7.36, p = 0.01)
indicated that LSD also impaired the recognition of sad faces,
but post hoc comparisons of the two dose groups with
placebo did not reach significance. No significant effects of
LSD on the decoding of neutral, happy, or angry facial
expressions were found.
Empathy
The effects of LSD on explicit emotional and cognitive
empathy are shown in Figure 2. Data were missing from 2 of
the 24 subjects in the 100 g LSD dose group because of
technical problems. There were significant main effects of
drug on explicit and implicit emotional empathy ratings
2641
(F1,36 = 14.05, po0.001 and F1,36 = 6.71, p = 0.01, respectively), indicating that LSD increased both aspects of
emotional empathy. The post hoc tests showed that the
200 g dose but not the 100 g dose of LSD produced a
significant effect on explicit (po0.01) and implicit (p = 0.01)
empathy scores compared with placebo. The valence-specific
analysis showed that LSD significantly increased explicit and
implicit emotional empathy scores for positive emotional
stimuli ( F1,36 = 24.32, po0.001 and F1,36 = 10.47, po0.01,
respectively) but there were only trend effects for negative
emotional stimuli (F1,36 = 3.29, p = 0.08 and F1,36 = 2.82,
p = 0.1, respectively). LSD decreased cognitive empathy,
reflected by a significant main effect of drug (F1,36 = 16.87,
po0.001). The post hoc tests showed that this effect was
significant for both the 100 and 200 g doses compared with
the respective placebo conditions (both po0.05).
Neuropsychopharmacology
2642
Figure 3 Subjective effects of lysergic acid diethylamide (LSD) over time on the Visual Analog Scales (VASs). LSD or placebo was administered at t = 0. The
data are expressed as mean SEM in 24 and 16 subjects in the 100 and 200 g LSD dose groups, respectively. LSD significantly increased ratings on all VASs
with significant doseresponse effects, except for ratings of happy. The corresponding maximal effects and statistics are shown in Table 1. Emotion
recognition (Face Emotion Recognition Task), empathy (Multifaceted Empathy Test), and social value orientation (SVO) tests were conducted 56 and 78 h
after the administration of the 100 and 200 g LSD dose, respectively. +/*po0.05, ++/**po0.01, +++/***po0.001 for the 100/200 g LSD dose,
respectively, compared with placebo (T-tests).
DISCUSSION
LSD positively altered the processing of emotional information by decreasing the recognition of fearful and sad faces
and enhancing emotional empathy and prosociality. We are
aware of no other published data on the acute effects of LSD
on emotion processing. However, MDMA produced very
similar effects to those of LSD in the present study. MDMA
reduced the recognition of sad and fearful faces but not
happy faces on the FERT (Bedi et al, 2010; Hysek et al,
2014b), increased explicit and implicit emotional empathy on
the MET (Hysek et al, 2014a; Kuypers et al, 2014) (mainly for
positive emotionally charged situations) (Hysek et al, 2014a;
Neuropsychopharmacology
2643
Table 1 Values and Statistics for the Subjective and Cardiovascular Peak Effects
Placebo 100 g
(mean SE)
LSD 100 g
(mean SE)
Placebo 200 g
(mean SE)
LSD 200 g
(mean SE)
Drug
Drug Dose
F1,38 =
p=
F1,38 =
p=
1939
***
6.21
Subjective effects
Visual Analog Scales (VAS, %)
Any drug effect
0.9 0.6
87.5 3.3***
0.1 0.1
97.2 1.7***#
0.9 0.6
85.2 3.4***
0.1 0.1
96.8 1.5***##
1661
***
7.66
**
0.0 0.0
17.3 3.6**
0.1 0.06
40.0 8.2***###
51.17
***
8.01
**
Fear
0.0 0.0
8.4 2.3
31.3 8.6***###
27.74
***
9.24
**
Happy
1.2 0.6
30 3.4***
5.0 2.0
39.1 4.2***
141.5
***
NS
Closeness to others
0.0 0.0
15.2 3.2***
4.3 1.8
32.3 4.7***###
61.68
***
5.38
Open
0.2 0.2
17.0 2.8***
3.9 1.5
41.0 3.6***###
128.9
***
18.4
***
Trust
0.0 0.0
22.0 4.1***
4.8 2.1
39.8 4.0***###
81.37
***
4.2
I want to be hugged
0.0 0.0
8.8 2.7
3.4 1.9
27.8 6.8***###
23.52
***
5.13
0.0 0.0
10.4 2.7*
27.6 6.1***##
41.21
***
9.13
**
0.06 0.1
1.4 3.3
I want to be alone
0.6 0.6
7.7 2.5
5.1 1.9
0.8 0.8
12.8 2.5**
10.8 4.2
0.0 0.6
2.5 1.0
17.6 5.6
42.8 5.5***###
9.93
**
0.76
NS
79.87
***
16.25
***
NS
2.3 0.5**
0.3 0.3
2.6 0.7
9.0 1.1**
1.3 1.1
Extroversion
0.5 0.3
Introversion
0.4 0.1
Fear
Dreaminess
1.8 0.7
0.3 0.2
0.1 0.1
0.2 0.3
0.1 0.6
4.1 0.6***
0.9 0.3
6.9 0.7***
6.6 1.6*
4.7 1.0***##
10.6 2.7***
0.1 0.5
1.5 0.7
0.5 0.4
4.3 0.8***
0.4 0.3
0.8 0.5
1.3 1.0
11.49
**
1.11
53.5
***
4.77
30.82
***
1.05
NS
2.67
NS
0.77
NS
51.92
***
0.01
NS
9.51
**
0.72
NS
7.9 0.6***
160.2
***
0.11
NS
Vital signs
Systolic blood pressure (mm Hg)
129 2.0
142 2.1***
133 3.8
148 2.9***
63.8
***
0.13
NS
76.9 1.5
85.7 1.7***
78.2 2.0
87.6 1.9***
68.8
***
0.08
NS
70.6 1.8
79.1 2.7**
72.8 2.6
86.9 4.29***
33.7
***
2.05
NS
0.5 0.1
0.8 0.1**
0.3 0.1
0.7 0.1**
23.74
***
0.22
NS
6.1 0.2
6.9 0.1***
6.5 0.2
7.2 0.1***
61.08
***
0.81
NS
4.3 0.2
5.2 0.2***
4.6 0.2
5.6 0.2***
89.61
***
0.02
NS
0.5 0.3
9.8 1.8***
0.1 0.6
NS
38.37
***
0.2 0.3
0.4 0.2
0.4 0.4
3.7 1.4**
12.06
**
6.76
0.5 0.3
0.1 0.2
0.8 0.4
0.6 0.9
6.03
1.83
NS
Values are mean SEM of the peak or peak changes () from baseline in 40 subjects. Sixteen subjects participated in the high dose study (200 g) and 24 subjects in the
moderate dose study (100 g).
*for po0.05, **for po0.01, ***for po0.001 compared with placebo. # for po0.05, ## for po0.01, ### for po0.001 compared with LSD 100 g.
2644
Figure 4 Subjective effects on the Adjective Mood Rating Scale. Lysergic acid diethylamide (LSD) or placebo was administered at t = 0. The data are
expressed as mean SEM changes from baseline (1 h) in 24 and 16 subjects in the 100 and 200 g LSD dose groups, respectively. Emotion recognition
(Face Emotion Recognition Task), empathy (Multifaceted Empathy Test), and social value orientation (SVO) tests were conducted 56 and 78 h after the
administration of the 100 and 200 g LSD dose, respectively. The corresponding maximal effects and statistics are shown in Table 1. *po0.05, **po0.01,
***po0.001 compared with placebo (T-tests).
2645
ACKNOWLEDGMENTS
We acknowledge the assistance of M Arends in text
editing. The studies were registered at ClinicalTrials.gov
(NCT02308969, NCT01878942).
REFERENCES
Bedi G, Hyman D, de Wit H (2010). Is ecstasy an empathogen?
Effects of 3,4-methylenedioxymethamphetamine on prosocial
feelings and identification of emotional states in others. Biol
Psychiatry 68: 11341140.
Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE,
Barbosa PC, Strassman RJ (2015). Psilocybin-assisted treatment
for alcohol dependence: a proof-of-concept study. J Psychopharmacol 29: 289299.
Carhart-Harris RL, Kaelen M, Bolstridge M, Williams TM,
Williams LT, Underwood R et al (2016). The paradoxical
psychological effects of lysergic acid diethylamide (LSD). Psychol
Med 46: 13791390.
Carhart-Harris RL, Kaelen M, Whalley MG, Bolstridge M,
Feilding A, Nutt DJ (2015). LSD enhances suggestibility in
healthy volunteers. Psychopharmacology 232: 785794.
Dolder PC, Liechti ME, Rentsch KM (2015a). Development and
validation of a rapid turboflow LC-MS/MS method for the
quantification of LSD and 2-oxo-3-hydroxy LSD in serum and
urine samples of emergency toxicological cases. Anal Bioanal
Chem 407: 15771584.
Dolder PC, Schmid Y, Haschke M, Rentsch KM, Liechti ME (2015b).
Pharmacokinetics and concentration-effect relationship of oral LSD
in humans. Int J Neuropsychopharmacol (doi:10.1093/ijnp/pyv072).
Dziobek I, Rogers K, Fleck S, Bahnemann M, Heekeren HR, Wolf OT
et al (2008). Dissociation of cognitive and emotional empathy in
adults with Asperger syndrome using the Multifaceted Empathy
Test (MET). J Autism Dev Disord 38: 464473.
Frye CG, Wardle MC, Norman GJ, de Wit H (2014). MDMA
decreases the effects of simulated social rejection. Pharmacol
Biochem Behav 117: 16.
Gasser P, Holstein D, Michel Y, Doblin R, Yazar-Klosinski B,
Passie T et al (2014). Safety and efficacy of lysergic acid
diethylamide-assisted psychotherapy for anxiety associated with
life-threatening diseases. J Nerv Ment Dis 202: 513520.
Gasser P, Kirchner K, Passie T (2015). LSD-assisted psychotherapy
for anxiety associated with a life-threatening disease: a qualitative
study of acute and sustained subjective effects. J Psychopharmacol
29: 5768.
Griffiths RR, Johnson MW, Richards WA, Richards BD,
McCann U, Jesse R (2011). Psilocybin occasioned mystical-type
2646
Nichols DE (2016). Psychedelics. Pharmacol Rev 68: 264355.
Oehen P, Traber R, Widmer V, Schnyder U (2013). A randomized,
controlled pilot study of MDMA (3,4-methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant,
chronic post-traumatic stress disorder (PTSD). J Psychopharmacol 27: 4052.
Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A
(2008). The pharmacology of lysergic acid diethylamide: a review.
CNS Neurosci Ther 14: 295314.
Preller KH, Pokorny T, Krhenmann R, Dziobek I, Stmpfli P,
Vollenweider FX (2015). The effect of 5-HT2A/1a agonist
treatment on social cognition, empathy, and social decisionmaking. Eur Psychiatry 30(Suppl. 1): 22.
Schmid Y, Enzler F, Gasser P, Grouzmann E, Preller KH,
Vollenweider FX et al (2015). Acute effects of lysergic acid
diethylamide in healthy subjects. Biol Psychiatry 78(8): 544553.
Schmid Y, Hysek CM, Simmler LD, Crockett MJ, Quednow BB,
Liechti ME (2014). Differential effects of MDMA and
methylphenidate on social cognition. J Psychopharmacol 28:
847856.
Strajhar P, Schmid Y, Liakoni E, Dolder PC, Rentsch KM,
Kratschmar DV et al (2016). Acute effects of LSD on
circulating steroid levels in healthy subjects. J Neuroendocrinol
(doi:10.1111/jne.12374).
Neuropsychopharmacology